The history of the treatment of lymphoma is a storied one, filled with landmark therapeutic discoveries. From the mid-20th century experience with successful radiation treatment for Hodgkin’s lymphoma to the development of effective chemotherapy regimens and rituximab in the latter half of the century, treatment breakthroughs have altered the landscape for this heterogeneous group of diseases, bringing significantly improved survival for most, and for many, lasting cure.
This remarkable history includes clinical trials showing that intensive chemotherapy with autologous stem cell support improves survival for patients with diffuse large B-cell lymphoma who relapse after initial treatment. Autologous stem cell transplantation (ASCT) is now the standard of care for relapse in this group of patients.
Yet, despite numerous advances, a significant number of patients with aggressive non-Hodgkin’s lymphoma cannot be successfully treated. The International Prognostic Index (IPI), developed in the 1990s, identified 4 prognostic groups for patients with aggressive B-cell lymphoma, and showed 5-year survival rates of less than 50% for the high-intermediate and high risk groups. After the success of ASCT in the setting of relapsed disease, the debate turned to whether early myeloablative therapy for consolidation during first remission might provide improved overall survival for these two high risk subgroups. While numerous clinical trials have addressed this question, no conclusive guidelines have emerged.
In this week’s NEJM, Stiff et al report on their phase III trial comparing early autologous stem cell transplantation to standard chemotherapy in patients with aggressive non-Hodgkin’s lymphoma. Eligibility criteria included biopsy-confirmed non-Hodgkin’s lymphoma (8 subtypes were studied, although the majority of patients had diffuse large B-cell lymphoma), age 15 to 65 years, and age-adjusted high-intermediate or high risk classification in the International Prognostic Index. An initial group of 370 participants received 5 cycles of induction chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or R-CHOP (with rituximab, for patients with CD20+ disease). Partial or complete response was required to advance to randomization. Ultimately, 253 patients underwent stratified randomization based on IPI risk category, 128 to the control group and 125 to the transplantation group.
The trial results showed a statistically significant improvement in the estimated 2-year progression-free survival in the transplant group compared to the control group (69% vs. 55%), and no statistically significant difference in the estimated 2-year overall survival rate (74% vs. 71%). 18% of patients who had a relapse or progression after standard therapy received salvage treatment – often transplantation – that resulted in long-term progression-free survival. Subgroup analysis showed no differences in treatment effect, except for improved progression-free survival and overall survival in the high risk compared to the high-intermediate risk subgroup; this finding was not conclusive however, as the study was not sufficiently powered to address this question. Adverse events, as anticipated, included a markedly greater number of grade 3 and grade 4 toxic events in patients receiving transplantation.
The authors conclude that no overall survival benefit was obtained from early transplantation, likely due to the effectiveness of salvage transplantation. They note that state-of-the-art FDG-PET imaging for treatment response as well as on-going studies of new chemotherapeutic regimens will contribute to efforts to define the role of consolidative transplantation.
In an accompanying editorial, Dr. Noel Milpied of University Hospital Bordeaux, France recommends that selection of high risk patients for future studies of early transplantation reflect not solely IPI classification, but also more recently defined cellular and genetic prognostic factors.
NEJM Deputy Editor Dr. Dan Longo adds, “For the time being, the question of whether any subset of patients benefits from early use of high dose therapy appears to be largely resolved. The majority of patients can be treated with conventional dose combination chemotherapy with high-dose therapy reserved as second-line treatment for the subset that relapses. On the other hand, the small number of patients with a high-risk profile of clinical prognostic factors and the subset of patients with so-called double hit lymphomas (lesions in c-myc and bcl2) may experience benefit from early high-dose therapy. Additional studies in these subsets appear warranted.”